Almost half of new cancer diagnoses in adults in the U.S. in 1999 will be of three types: cancers of the lung, breast, and prostate. If significant progress is to be made in reducing total cancer incidence, it will be important to finds means of preventing these major tumors. Toward this end, basic scientists have identified a variety of genes in experimental systems that may be important in the etiology of these cancers. Concordantly, epidemiologists have identified environmental factors that are associated with increased cancer risk (e.g., smoking and lung cancer). In addition, statistical geneticists have shown that for a large number of malignancies, the risk of developing and surviving cancer is not uniformly distributed throughout the population. However, to date, it has been difficult to synthesize the results of these diverse studies. Few investigations have been comprehensive enough to incorporate both environmental risk factors and to examine the interactions among them. Thus, it is the objective of this project determine the role individual genetic variation plays in modifying the risk of cancer imposed by environmental factors. The ultimate goal of such studies will be the identification of individuals with genetically determined cancer susceptibility. To perform these studies, we are conducting a hospital-based case-control study. The goal is to obtain 1000 cases of each of the above cancer sites and a collection of 1000 controls. To date the study has accrued more than 500 breast cancer cases, 350 prostate cancer cases, 600 lung cancer cases, and 700 control samples. The study is identifying new DNA-based variation in an extended collection of detoxification genes which may mediate the carcinogenic effects of exogeneous and endogenous exposures. To date, studies have focused on GSTA1, GSTM1, GSTM3, GSTP, GSTT1, GST12, EPHX1, EPHX2. Each gene has been tagged with new or published polymorphisms. Once identified, tests for association of variation in candidate loci in cases when compared to sex-matched controls who are smokers and non- smokers will be conducted. Assessment of association dependent on case characteristics will be made. Using family history information obtained from each case and control reference individual, the patterns of cancer aggregation in families will be assessed. Finally, the relationship between aggregation within families and variation of candidate genes in the probands and their family members will be determined.